CA1296739C - Diphosphonic acid derivatives, processes for the preparation thereofand pharmaceutical compositions containing them - Google Patents
Diphosphonic acid derivatives, processes for the preparation thereofand pharmaceutical compositions containing themInfo
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- CA1296739C CA1296739C CA000541755A CA541755A CA1296739C CA 1296739 C CA1296739 C CA 1296739C CA 000541755 A CA000541755 A CA 000541755A CA 541755 A CA541755 A CA 541755A CA 1296739 C CA1296739 C CA 1296739C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
Abstract
ABSTRACT
Diphosphonates of the general formula:
Diphosphonates of the general formula:
Description
~L2~6'73~
The present invention is concerned wi~h new diphosphonic acid derlvatives, processes for the preparation thereof and pharmaceutical compositions containing them.
Federal Republic of Germany Patent Specifi-cation No. 18 13 659 describes dlphosphonic acid derivatives, of which l-hydroxyethane-l,l-diphos-phonic acid has achieved importance as an agent for the treatment of Paget's disease. Belgian Patent Specification No. 896,453, Federal Republic of Germany Patent Specification No. 25 34 391 and European Patent Specification No. 0,096,931 describe aminoalkane-l,1-diphosphonic acids as good calcium complex formers which can also be used for the treatment of increased bone resorption. ~Iowever, in the case of therapeutically effective dosages, such compounds frequently display side effects.
Consequently, there is a need to provide new aminoalkane-diphosphonates which manifest a therapeutic effectiveness at the lowest possible dosage level.
It has now been found that analogous - derivatives of these compounds with a tertiary amino group in which the nitrogen atom bears a first alkyl substituent and a second substituent selected from alkyl and benzyl in which such substituents together contain more than 3 carbon atoms, fulfil this requirement and can be used as good calcium complex formers for the broader treatment of calcium meta-bolism disturbances. In particular, they can be well used where the bone formation and breakdown is disturbed, i.e. they can be used for the treatment of ~q~
.
diseases of the skeletal system, for example, osteo-porosis, Paget's disease, Bechterew's diseases and the like.
However, on the basis of these properties, they can also be used for the therapy of bone meta-stases, urolithiasis and for the prevention of heterotopic ossifications. L~ue to thelr influence on calcium metabolism, they also form a basis for the treatment of rheumatoid arthritis, osteoarthritis and 10 degenerative arthrosis. ;~
Thus, according to the present invention, there are provided diphosphonates of the yeneral formula:
Rl o=P(oH)2 N C 2 2 1 (I) R2 o=P(OH)2 wherein Rl is methyl or n-propyl; and R2 is isobutyl, pentyl, nonyl or benzyl; as well as the pharmaceuti-cally acceptable, pharmacologically compatible salts thereof.
; Preferred compounds of general formula (I) according to the present invention are those in which Rl is a methyl radical and R2 is an isobutyl or pentyl radical, especially the compound l-hydroxy-3-(N-methyl-N-pentylamino)-propane-l,l-diphosphonic acid.
~ .
1~9~39 The compounds of general formula (I) according to the present invention can be prepared by known processes:
a) a carboxylic acid of the general formula:
N -- CH2CH2 - COOH (VIII ) ,.
wherein Rl and R2 have the above-given meanings, is reacted with a mixture of phosphorous acid or phos-: phoric ac:id and a phosphorus halide, and subsecluently saponified or hydrolyzed to a ~ree diphosphonic acid of formula (I); or b) a carboxylic acid chloride of the general formula:
Rl N - CH2CH2 - COCl (IX) R2 '~
, ; wherein Rl and R2 have the above-given meanings, is reacted with a trialkyl phosphite of the general formula:
~(OR')3 (X) :
wherein R' is an alkyl radical of 1 to 4 carbon atoms to give an acyl phosphonate o~ the general formula:
~;i ,~
~L2~i73~
- N - CH CH - C - P(OR')2 (XI) wherein R1, R2 and R' have the above-given meanings, subsequently reacted with a dialkyl phosphite of the general formula:
~: O
H - P(OR')2 (XII), wherein R' has the above-given meaning, to give a diphosphonate of the general Eormula:
Rl 0 = P(OR')2 '1 N - CH2CH2 - C - OH (XIII) R2 0 = P(OR')2 wherein Rl, R2 and R' have the above-given meanings, and the resultant tetraester is optionally saponified or hydrolysed to the corresponding free acid of general formula (I): or ~2~39 ~
c) a compound of the general formula:
o = P(OR')2 R4 NH CH2C 2 1 (XIV) O P(OR )2 . .
wherein R' has the above-given meaning and R4 is a hydro~en atom or has the same meaning as R2, is mono-or dialkylated and the resultant tetraester is optionally saponified or hydrolysed to the corres-ponding ~ree acid of general formula (I); and, iE
desired, the compounds thus prepared are converted into their pharmaceutically accepkable, pharmaco-loyically compatible salts.
:The carboxylic acids of general formula (VIII) used in process a) are suitably reacted with 1 to 2 and preferably 1.5 mole phosphorous acid or phosphoric acid and 1 to 2 and preferably 1.5 mole : phosphorus trihalide at a temperature of from 80 to 130C. and preferably of from 100 to 110C. The reaction can also be carried out in the presence of diluents, for example, halogenated hydrocarbons, especially chlorobenzene or tetrachloroethane, or also dioxan.
In the case of process b), the acid chlo-ride of general formula (IX) is suitably reacted with the trialkyl phosphite of general formula (X) at a temperature of from 0 to 60C. and preferably of from 20 to 40C. The reaction can be carried out without :a solvent or also in the presence of inert solvents, .~
~ ,.
for example, diethyl ether, tetrahydrofuran, dioxan or also halogenated hydrocarbons, for example, methylene chloride. The acyl phosphonate of general formula (XI) formed as intermediate can be isolated or further reacted directly. The subsequent reaction is carried out in the presence of a weak base, preferably of a secondary amine, for example, dibutylamine, at a temperature of from O to 60C. and preferably of from 10 to 30C.
As phosphorus trihalides in the above-mentioned processes, there can be used, for example, phosphorus trichloride or phosphorus tribromine.
In the case of the reductive alkylation accord:ing to process c), a mixture oE primary or secondary amine oE general formula (XIV) and of a carbonyl compound or oE an acetal thereof is suitably treated in the presence of a hydroqenation catalyst, for example, palladium on charcoal or nickel, with hydrogen at atmospheric or increased pressure or with the use of formic acid as reducing agent. Sub-sequently, alkylation of a secondary amine of general formula ~XIV) can be carried out especially advan-tageously according to the phase transfer process with dialkyl sulphates.
The tetraalkyl esters possibly obtained can be saponified or hydrolysed to the corresponding free tetra acids.
The hydrolysis to the free diphosphonic acids usually takes place by boiling with hydro-; 30 chloric or hydrobromic acid. However, a cleavage ~ with a trimethylsilyl halide, preferably the bromide ; or iodide, can also be carried out. On the other hand, the free diphosphonic acids can be converted ,,~
~L
again into ~he tetraalkyl esters by boiling withorthoformic acid alkyl esters. The free diphosphonic acid oP general formula (I) can be :isolated as the free acids or in the form of their mono- or dialkali metal salts. The alkali metal salts can usuall~ be readily purified by reprecipitation from water/-methanol or from water/acetone.
As pharmaceutically acceptable, pharmaco-; logically compatible salts, there are preferably used 10 the alkali metal or ammonium salts which can be prepared in the usual way, for example, by titration of the compounds with inorganic or organic bases, for exarnple, sodium or potassium hydrogen carbonates, aqueous solutions of sodium or potassium hydroxides or aqueous solut:ions of ammonia or oP amines, I.or example, trimethyl or triethylamine.
In the specification :it will be understoodthat the qualification that the salts be "pharma-ceutically acceptable" means that the salts have the 20 necessary physical characteristics, for example, stability to render them suitable for formulation into pharmaceutical compositions. The qualification that the salts be "pharmacologically compatible" is to be understood, as extending to salts of non-toxic inorganic or organic cations or base components which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies.
Salts of compounds of formula (I) which are 30 not pharmaceutically acceptable and pharmacologically compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, by conventional means, to dif-~ .
".
,l...,~
3~
ferent salts having the required physical andchemical characteristics to make them suitable for administration in pharmaceutical compositions to living bodies.
The new compounds of general formula (I) according to the present invention and the salts thereof can be administered enterally or parenterally in liquid or solid form. For this purpose, there can be used all conventional forms of administration, for 10 example, tablets, capsules, drageesr syrups, solutions, suspensions and the like. As in~ection medium, it is preferred to use water which contains the additives usual in the case of injection solutions, Eor examaple, stabilising agen-ts, solubi-lising ayents and buEfers. Additives oE this kind include, for example, tartrate and citrate buEfers, ethanol, complex formers (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and ~high molecular weight polymers (such as liquid ;20 polyethylene oxide) for viscosity regulation. Liquid carrier materials for in~ection solutions must be sterile and are preferably placed in ampoules. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycol). Compositions 30 suitable for oral administration can, if desired, also contain flavouring and sweetening agents.
~ .
!
~ fi7~
_ 9 _ The dosage can depend upon various factors, such as the mode of administration, species, age and/or indlvidual condition. The dosage to be administered daily are about l to 1000 mg. in the case of humans and pxeferably 10 to 200 mg and can be given one or several times per day.
In order to demonstrate the activity of the compounds (I) male Wistar rats bred on behalf of the ; Applicant and weighing about 160 g were thyropara-10 thyroidectomized on day l. On day 5, the success of the operation was controlled by measuring calcemia after a night fasting. From that day on, all the animals were group fed, that means all of them ate the same ~uantity of food. Furthermore, the anima:Ls received dai:Ly ~or 3 days 2 subcutaneous in~ections, one containing 25 \ug of a synthetic retinoid, the other the bisphosphonate (I) to be tested.
Additionally, all animals were given 2 ~ug of thyroxine the first and last day of treatment. 24 20 hours after the last injection of the retinoid and the bisphosphonates (I) and after one night fasting, ~; blood was taken by retroorbital puncture under ether anesthesia. Plasma calcium was then analyzed by means of atomic absorption.
The bisphosphonates (I) were given first at a dose of 0.1 mg P/kg in a volume of 2 ml/kg, the less active also at 1 to 10 mg P/kg.
Table I below shows the results for parti-cular compounds (I) of the subsequent Examples.
~$~
TABLE
Depression of hypercalcaemie (in mg%) at various dosages administered ;:
_ Example dosaye [mg P/kg] :
0.01 0.0 1 2 1.75 5.74 6 2.26 S.90 8 0.49 1.74 9A 4.59 7.34 9B 3.36 6.06 . ............... .
13 0.69 4.34 15A 1.99 3.09 16B 1.43 3.12 . i 3~
The following Examples illustrate some of the process variants which can be used for the synthesis of the compounds according to the present invention as well as related compound, the latter serving as Reference Examples. The structures of these compounds were verified by H- and P-NMR
spectroscopy and the purity by means of p-NMR
spectroscopy, thin layer electrophoresis (cellulose, oxalate buffer of pH 4.0) and by means of C, H, N, P
10 and Na analyses. For the characterization of the individual compounds, there are given the Mrel values (relative mobilities) referred to pyrophosphate (Mr~el = 1.0).
.
r~
3L2:~3 ExamPle l~(Referenc~) diphosphonic acid.
13.3 g. 3-~,N-Dipentylaminopropionic acid are kept for 20 hours at looc~ with 7.1 g. phosphorous acid and 14,8 ml. phosphorus trichloride in 67 ml.
chlorobenzene. The solvent is then decanted of and the re~idue is stirred under reflux with 180 ml. 6N hydro-chloric acid for 8 hou,rs. Insoluble material i9 filtered off and the filtrate is concentrated and applied to a column of ~mberlite*IR 120 (H+ Eorm). ~he elution with water is monitored electrophoretically.
The desired fractions are combined, evaporated and stirred up with acetone and the crystals obtained are isolated. There are thus obtained 12.9 g. of crude product. After recrystallising twice ~rom water, -there are obtained 4.7 g. ( 220~o of theory) of analytically pure product in the form of the hemihydrate, m.p. 114C.
with sintering, 189 - 191C. (decomp.), Mrei = .24.
The starting material is obtained as follows:
Dipentylamine is reacted with methyL acrylate in toluene in the mole ratio of 1:3. There is obtained a yield of 28% of theory of the oily dipentylaminopropionic acid ester which is saponified with lN aqueous sodium hydroxide solution to give a yield of 56% of theory of * Trade Mark 1~ .
hr 3l~3 ~6 the desired acid, m.p. 47 - 49C.
~.
diphosphonic acid.
S In a manner analogous to that described in Reference Example 1, from 3-~-methyl-N-nonylaminopropionic acid there is obtained the corresponding diphosphonate in a yield of 10% of theory, m.p. 159C. with sintering, 178 - 184 C., Mrel = 0-22-l'he ~tarting material is obtained as follows:
Nonylamine i9 reacted~with benzaldehyde to give the oily Schiff base in a yield of 9~% of theory. Hydrogenation with palladium-charcoal catalyst gives l~-benzyl-N-nonyl-amine as an oil in a yield of 94% of theory. From this, with formaldehyde and formic acid, there is-obtained the oily N-benzyl-N-methyl-N-nonylamine in a yield of 98~ of theory. Hydrogenolytic splitting off of the benzyl radical with palladium-charcoal catalyst gives a quantitative yield of the secondary amine in the form of an oil which is reacted with methyl acrylate and saponified in the manner described in Example 1. The yield of the oily ester is 81% of theory and that of the pasty acid is 95O/o of theory.
Exam~le 3.(Reference) 2S 3-~N-Cyclohexyl-N-methylamino~ hydroxy~ropane~
di hos honic acid.
15 g. 3-N-Cyclohexyl-N-methylaminopropionic acid ~ 1 73~
. ., "~prepared from N-cycloh~yl-N-methylamine (commercially - . . available) and methyl acrylate in toluene, yield oE
e~ter 76% o~ theo~y, m.p. 131 - 134C., yield of acid 92% of theory, m.p. 101 - 105C,) are heated to 80C.
with 13.3 g. phosphorous acid. The melt i5 mixed with - 14.1 ml. phosphorus trichloride and kept at the same - temperature for 16 hours. 240 ml. water are then added thereto and the reaction mixture i~ stirred for 1 day at 100C. It is then filtered, the filtrate i~ concen-trated in a vacuum and the oil obtained is poured into 1 litre of acetone, c~ystallisation thereby commencing.
~he crystals are dissolved in water and puriied by ion exchanger chromatography in the manner described in Example 1~ Yield 4.5 g. ~16~90~o of theory) as mono-lS hydrate, m.p. 142C. with sintering, 182 C. (decomp.), Mrel Example 4. (Reference) 1 g. 3-N-Cyclohexylaminopropane-l-hydroxy-l,l-diphosphonic acid is suspended in 30 ml. methylene chloride, 2.5 ml. of a concentrated aqueous solution of sodium hydroxide are added thereto and, with cooling, mixed with 1 g. tetrabutylammonium hydrogen suLphate and 0.3 ml. dimethyl sulphate. The reaction mixture is then vigorously stirred for several hours at ambient temperature. After working up in the usual manner, the identicity of the product obtained with that prepared according to Example 3 is demonstrated by mass spectro- ;
F
.
~: ;. . .
673~
., .
scopy ater siLylation.
The diphosphonic acid used as starting material i9 obtained a~ ~ollows: Cyclohexylamine is reacted with acrylic acid in pyridine to give a yleld of 7~/0 - 5 of theory of 3~N-cyclohexylaminopropionic acid, m.p.
170 - 171C~ The reaction with phosphorou~ acid and phosphorus trichloride gives a yield of 31% of theory of the diphosphonic acid, m.p. 164C. (decomp.l.
Ex~ple ~. (Reference) 10 3-(N Cvc~ohexylmethvl-N-methYlamino)-propane-l-hydroXV- ;`
l,l-diphos~honic acid., 3 ~N-Cyclohexylmethyl-N-methylamino)-propionic acid (prepared ~rom N-benzyl-N-methylamine by hydrogen-ation with platinum catalyst, yield 70% of theory, b.p.
60C./16 mm.Hg reaction with methyl acrylate in toluene, yield 37% of theory o~ methyl 3-(N-cyclohexyl-methyl-~-methylamino)-propionate, saponification with lN aqueous sodium hydroxide solution to give the acid in a yield of 63% o~ theory, m.p. 98 - 102C,) is reacted analogously to Example 3 with phosphorous acid/
phosphorus trichloride to give the diphosphonic acid in a yield of 34% of theory, m.p. 180 - 194C. (decomp.), ~réi ~ 0.31.
~.
di~ ~ acid.
In a manner analogous to that descxibed in i739 Example 3, ~rom 3~N-nonyl-N-propylaminopropionic acid there is obtained the correi~po~ding diphosphonic acid in a yield of 50% of theory, m.p. 100 -- 105C., ~ M 1 = o.23.
- The starting material is obtained ais follows:
2 mole nonylamine are reacted with 1 mole propionyl - chloride to give a quantitative yield o~ the acid amide whlch is reduced with lithium aluminium hydride tD give the secondary amine in a yield of 71% of theory, b.p.
113 - 117C./16 n~.Hg. l mole N-Ilonyl-N-propylamine i9 reacted with 3 mole methyl acrylate in toluene to give an oil in a yield of 81% of theory whIch i9 saponified with lN aqueous sodium hydroxide solution - to give the desired acid in a yield of 14% of theory, m.p. 45 - 47C.
.(Reference) 500 mg. of the diphosphonic acid prepared accord-ing to Example 1 are suspended in 5 ml. water, dissolved with 2.68 ml. 1~ aqueous sodium hydroxide solution, concentrated somewhat and brought to crystallisation by pouxing into aretone. There are thus obtained 440 mg. (78% of theory) of the disodium salt of 1-hydroxy-3-(N,N-dipentylamino)-propane~ diphoisphonic acid in the form of the monohydrate. The meltiny point is above 300C.
Exam~ eference) ~ '~
di~hos~honic acid.
~ .
~L2~ 3~
2 mole nonylamine are reacted with 1 mole valeroyl chloride in diethyl ether, the su3pension is filtered ~ff with suction, the filtrate is evapoxated and N-nonyl-valeric acid amide is thus obtained quantitatively, m.p.
29 - 31C. Reductlon with 1.65 mole lithium aluminium hydride in diethyl ether gives a colourle~s oil in a yield of 78% of theory, b.p. 142 ~ 1~6 Co/16 mm.Hg.
The addition of this N-nonyl-N-pentylamine to methyl acrylate (oil, yield 96% of theory) an~ subsequent ~aponification with lN aqueous sodium hydroxide solution gives a yield of 6~% o~ theory of pasty 3-(N-nonyl-~-pentylamino)-propionic acid ~hich is reacted analogously to Example 3 to give the diphosphonic acid, yield 87%
of theory; m.p. 168 - 17~ C., Mrel = 0.14.
Example 9.
; In a manner analogous to that described in Example 2, there are prepared:
yield m.p.
A. In ~ products:
20 N-benzylidenepentylamine 94% oil N-benzyl-N-pentylamine 74% paste N-benzyl-N-methyl-N-pentylamine 95% oil ~-methyl-N-pentylamine 49% oil methyl 3-(N-methyl-N-pentylamino)- 93% oil propionate 3-(N-methyl-N-pentylaminO)-propionic 34% deliquescent acid crystals ~L;2~'Fi'7~9 ~ yield mO p .
l-hydroxy-3-(N-methyl N-pentylamino)- Mrel 84 C.
propan~-l,l-diphosphonic acid 0 44 decomp.
S B. I termediate products:
N-benzylideneisobutylamine 96% oil N-benzyl-N-isobutylamine 71% oil ~-benzyl-N-isobutyl-N-methylamine 93% oil N-isobutyl-N-methylamine 96% oil 10 methyl 3-(N-isobutyl~N-methylamino)- 9~/ oil propionate 3-(N-isobutyl-N-methylamino)- S7% oil propionic ~cid End product:
1-hydroxy-3-lN-isobutyl-N-methylamino)- Mrel 140C
propane-l,l-diphosphonic acld decomp.
yield C. Intermediate products(Reference):
N-benzylidenehexadecylamine 85% oil 20 N-benzyl-N-hexadecylamine 76% wax N-benzyl-N-hexadecyl-N-methylamine 93% oil N-hexadecyl-N-methylamine 98% wax methyl 3-(N-hexadecyl-N-methylamino)- 100% wax propionate 3-(N-hexadecyl-N-methylamino)- 37% 58-60C.
propionic acid End ~roduct:
3-(N-hexadecyl-N-methylamino)-propane- Mrel 198-254C.
l-hydroxy-l,l-diphosphonic acid o,l decomp.
72%
~2~3~
The oily intermediate products are further reacted without distillation~ The purification of the end products is carried out by ion ~xchange chromatography.
Ex ~ . (Reference) 3_N/N ~ propane-l-hydroxy~ diphosphonic acid.
In a manner analogous to that de~cribed in Reference Example 3, from 3-N,N-dinonylaminopropionic acid there i9 obtained the corresponding diphosphonic acid as the hemihydrate in a yield of 49% of theorY; m.p. 83C.
sintsrs, 161 - 171C,,melts with gas evolution, ~rel =
0.16.
The reaction sequence for the preparation of the starting material is analogous to that described in Example 6:
pelargonic acid N-nonylamide, yield 100% o~ theory, m.p, 52 - 55C.
N,N-dinonylamide, yield 79% of theory, m.p. 37 - 39C.
methyl 3-N,N-dinonylamihopropionate, yield 71% of theory, oil 3~N,~-dinonylaminopropionic acid, yield 180/o of theory, deliquescent crystals.
Example 11~ (Reference) l-Hydroxy-3=(N-meth~l-N-propylamino)-propane-l~l-di hos honic acid _~-: In a manner analogous to that described inReference Example 3, from 3-(~-methyl-N-propylamino)-propionic F
~2~7~9 acid there i~ obtained the corresponding diphosphonic acid in a yield of 35% of theory in the form of the 3es~uihydrate, m.p. 108C. (decomp,) Mrel = 0.4.
The starting material is obtained as follows:
N-methyl-N-propylamine (J.A.C.S., 79, 4720/1957) is reacted, analogously to Example 1, with methyl acrylate and the ester obtained in a yield of 840/o of theory is, without distillation, saponified with lN a~ueous sodium hydroxide solution. The oily acid is thus obtained in a yield of 92% of theory and is used without further purification.
.(Reference) l-Hydrox~-4-(N,N-di-3-methylbut~lamino)-butane-1,1-di~hosphonic acid.
The present invention is concerned wi~h new diphosphonic acid derlvatives, processes for the preparation thereof and pharmaceutical compositions containing them.
Federal Republic of Germany Patent Specifi-cation No. 18 13 659 describes dlphosphonic acid derivatives, of which l-hydroxyethane-l,l-diphos-phonic acid has achieved importance as an agent for the treatment of Paget's disease. Belgian Patent Specification No. 896,453, Federal Republic of Germany Patent Specification No. 25 34 391 and European Patent Specification No. 0,096,931 describe aminoalkane-l,1-diphosphonic acids as good calcium complex formers which can also be used for the treatment of increased bone resorption. ~Iowever, in the case of therapeutically effective dosages, such compounds frequently display side effects.
Consequently, there is a need to provide new aminoalkane-diphosphonates which manifest a therapeutic effectiveness at the lowest possible dosage level.
It has now been found that analogous - derivatives of these compounds with a tertiary amino group in which the nitrogen atom bears a first alkyl substituent and a second substituent selected from alkyl and benzyl in which such substituents together contain more than 3 carbon atoms, fulfil this requirement and can be used as good calcium complex formers for the broader treatment of calcium meta-bolism disturbances. In particular, they can be well used where the bone formation and breakdown is disturbed, i.e. they can be used for the treatment of ~q~
.
diseases of the skeletal system, for example, osteo-porosis, Paget's disease, Bechterew's diseases and the like.
However, on the basis of these properties, they can also be used for the therapy of bone meta-stases, urolithiasis and for the prevention of heterotopic ossifications. L~ue to thelr influence on calcium metabolism, they also form a basis for the treatment of rheumatoid arthritis, osteoarthritis and 10 degenerative arthrosis. ;~
Thus, according to the present invention, there are provided diphosphonates of the yeneral formula:
Rl o=P(oH)2 N C 2 2 1 (I) R2 o=P(OH)2 wherein Rl is methyl or n-propyl; and R2 is isobutyl, pentyl, nonyl or benzyl; as well as the pharmaceuti-cally acceptable, pharmacologically compatible salts thereof.
; Preferred compounds of general formula (I) according to the present invention are those in which Rl is a methyl radical and R2 is an isobutyl or pentyl radical, especially the compound l-hydroxy-3-(N-methyl-N-pentylamino)-propane-l,l-diphosphonic acid.
~ .
1~9~39 The compounds of general formula (I) according to the present invention can be prepared by known processes:
a) a carboxylic acid of the general formula:
N -- CH2CH2 - COOH (VIII ) ,.
wherein Rl and R2 have the above-given meanings, is reacted with a mixture of phosphorous acid or phos-: phoric ac:id and a phosphorus halide, and subsecluently saponified or hydrolyzed to a ~ree diphosphonic acid of formula (I); or b) a carboxylic acid chloride of the general formula:
Rl N - CH2CH2 - COCl (IX) R2 '~
, ; wherein Rl and R2 have the above-given meanings, is reacted with a trialkyl phosphite of the general formula:
~(OR')3 (X) :
wherein R' is an alkyl radical of 1 to 4 carbon atoms to give an acyl phosphonate o~ the general formula:
~;i ,~
~L2~i73~
- N - CH CH - C - P(OR')2 (XI) wherein R1, R2 and R' have the above-given meanings, subsequently reacted with a dialkyl phosphite of the general formula:
~: O
H - P(OR')2 (XII), wherein R' has the above-given meaning, to give a diphosphonate of the general Eormula:
Rl 0 = P(OR')2 '1 N - CH2CH2 - C - OH (XIII) R2 0 = P(OR')2 wherein Rl, R2 and R' have the above-given meanings, and the resultant tetraester is optionally saponified or hydrolysed to the corresponding free acid of general formula (I): or ~2~39 ~
c) a compound of the general formula:
o = P(OR')2 R4 NH CH2C 2 1 (XIV) O P(OR )2 . .
wherein R' has the above-given meaning and R4 is a hydro~en atom or has the same meaning as R2, is mono-or dialkylated and the resultant tetraester is optionally saponified or hydrolysed to the corres-ponding ~ree acid of general formula (I); and, iE
desired, the compounds thus prepared are converted into their pharmaceutically accepkable, pharmaco-loyically compatible salts.
:The carboxylic acids of general formula (VIII) used in process a) are suitably reacted with 1 to 2 and preferably 1.5 mole phosphorous acid or phosphoric acid and 1 to 2 and preferably 1.5 mole : phosphorus trihalide at a temperature of from 80 to 130C. and preferably of from 100 to 110C. The reaction can also be carried out in the presence of diluents, for example, halogenated hydrocarbons, especially chlorobenzene or tetrachloroethane, or also dioxan.
In the case of process b), the acid chlo-ride of general formula (IX) is suitably reacted with the trialkyl phosphite of general formula (X) at a temperature of from 0 to 60C. and preferably of from 20 to 40C. The reaction can be carried out without :a solvent or also in the presence of inert solvents, .~
~ ,.
for example, diethyl ether, tetrahydrofuran, dioxan or also halogenated hydrocarbons, for example, methylene chloride. The acyl phosphonate of general formula (XI) formed as intermediate can be isolated or further reacted directly. The subsequent reaction is carried out in the presence of a weak base, preferably of a secondary amine, for example, dibutylamine, at a temperature of from O to 60C. and preferably of from 10 to 30C.
As phosphorus trihalides in the above-mentioned processes, there can be used, for example, phosphorus trichloride or phosphorus tribromine.
In the case of the reductive alkylation accord:ing to process c), a mixture oE primary or secondary amine oE general formula (XIV) and of a carbonyl compound or oE an acetal thereof is suitably treated in the presence of a hydroqenation catalyst, for example, palladium on charcoal or nickel, with hydrogen at atmospheric or increased pressure or with the use of formic acid as reducing agent. Sub-sequently, alkylation of a secondary amine of general formula ~XIV) can be carried out especially advan-tageously according to the phase transfer process with dialkyl sulphates.
The tetraalkyl esters possibly obtained can be saponified or hydrolysed to the corresponding free tetra acids.
The hydrolysis to the free diphosphonic acids usually takes place by boiling with hydro-; 30 chloric or hydrobromic acid. However, a cleavage ~ with a trimethylsilyl halide, preferably the bromide ; or iodide, can also be carried out. On the other hand, the free diphosphonic acids can be converted ,,~
~L
again into ~he tetraalkyl esters by boiling withorthoformic acid alkyl esters. The free diphosphonic acid oP general formula (I) can be :isolated as the free acids or in the form of their mono- or dialkali metal salts. The alkali metal salts can usuall~ be readily purified by reprecipitation from water/-methanol or from water/acetone.
As pharmaceutically acceptable, pharmaco-; logically compatible salts, there are preferably used 10 the alkali metal or ammonium salts which can be prepared in the usual way, for example, by titration of the compounds with inorganic or organic bases, for exarnple, sodium or potassium hydrogen carbonates, aqueous solutions of sodium or potassium hydroxides or aqueous solut:ions of ammonia or oP amines, I.or example, trimethyl or triethylamine.
In the specification :it will be understoodthat the qualification that the salts be "pharma-ceutically acceptable" means that the salts have the 20 necessary physical characteristics, for example, stability to render them suitable for formulation into pharmaceutical compositions. The qualification that the salts be "pharmacologically compatible" is to be understood, as extending to salts of non-toxic inorganic or organic cations or base components which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies.
Salts of compounds of formula (I) which are 30 not pharmaceutically acceptable and pharmacologically compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, by conventional means, to dif-~ .
".
,l...,~
3~
ferent salts having the required physical andchemical characteristics to make them suitable for administration in pharmaceutical compositions to living bodies.
The new compounds of general formula (I) according to the present invention and the salts thereof can be administered enterally or parenterally in liquid or solid form. For this purpose, there can be used all conventional forms of administration, for 10 example, tablets, capsules, drageesr syrups, solutions, suspensions and the like. As in~ection medium, it is preferred to use water which contains the additives usual in the case of injection solutions, Eor examaple, stabilising agen-ts, solubi-lising ayents and buEfers. Additives oE this kind include, for example, tartrate and citrate buEfers, ethanol, complex formers (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and ~high molecular weight polymers (such as liquid ;20 polyethylene oxide) for viscosity regulation. Liquid carrier materials for in~ection solutions must be sterile and are preferably placed in ampoules. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycol). Compositions 30 suitable for oral administration can, if desired, also contain flavouring and sweetening agents.
~ .
!
~ fi7~
_ 9 _ The dosage can depend upon various factors, such as the mode of administration, species, age and/or indlvidual condition. The dosage to be administered daily are about l to 1000 mg. in the case of humans and pxeferably 10 to 200 mg and can be given one or several times per day.
In order to demonstrate the activity of the compounds (I) male Wistar rats bred on behalf of the ; Applicant and weighing about 160 g were thyropara-10 thyroidectomized on day l. On day 5, the success of the operation was controlled by measuring calcemia after a night fasting. From that day on, all the animals were group fed, that means all of them ate the same ~uantity of food. Furthermore, the anima:Ls received dai:Ly ~or 3 days 2 subcutaneous in~ections, one containing 25 \ug of a synthetic retinoid, the other the bisphosphonate (I) to be tested.
Additionally, all animals were given 2 ~ug of thyroxine the first and last day of treatment. 24 20 hours after the last injection of the retinoid and the bisphosphonates (I) and after one night fasting, ~; blood was taken by retroorbital puncture under ether anesthesia. Plasma calcium was then analyzed by means of atomic absorption.
The bisphosphonates (I) were given first at a dose of 0.1 mg P/kg in a volume of 2 ml/kg, the less active also at 1 to 10 mg P/kg.
Table I below shows the results for parti-cular compounds (I) of the subsequent Examples.
~$~
TABLE
Depression of hypercalcaemie (in mg%) at various dosages administered ;:
_ Example dosaye [mg P/kg] :
0.01 0.0 1 2 1.75 5.74 6 2.26 S.90 8 0.49 1.74 9A 4.59 7.34 9B 3.36 6.06 . ............... .
13 0.69 4.34 15A 1.99 3.09 16B 1.43 3.12 . i 3~
The following Examples illustrate some of the process variants which can be used for the synthesis of the compounds according to the present invention as well as related compound, the latter serving as Reference Examples. The structures of these compounds were verified by H- and P-NMR
spectroscopy and the purity by means of p-NMR
spectroscopy, thin layer electrophoresis (cellulose, oxalate buffer of pH 4.0) and by means of C, H, N, P
10 and Na analyses. For the characterization of the individual compounds, there are given the Mrel values (relative mobilities) referred to pyrophosphate (Mr~el = 1.0).
.
r~
3L2:~3 ExamPle l~(Referenc~) diphosphonic acid.
13.3 g. 3-~,N-Dipentylaminopropionic acid are kept for 20 hours at looc~ with 7.1 g. phosphorous acid and 14,8 ml. phosphorus trichloride in 67 ml.
chlorobenzene. The solvent is then decanted of and the re~idue is stirred under reflux with 180 ml. 6N hydro-chloric acid for 8 hou,rs. Insoluble material i9 filtered off and the filtrate is concentrated and applied to a column of ~mberlite*IR 120 (H+ Eorm). ~he elution with water is monitored electrophoretically.
The desired fractions are combined, evaporated and stirred up with acetone and the crystals obtained are isolated. There are thus obtained 12.9 g. of crude product. After recrystallising twice ~rom water, -there are obtained 4.7 g. ( 220~o of theory) of analytically pure product in the form of the hemihydrate, m.p. 114C.
with sintering, 189 - 191C. (decomp.), Mrei = .24.
The starting material is obtained as follows:
Dipentylamine is reacted with methyL acrylate in toluene in the mole ratio of 1:3. There is obtained a yield of 28% of theory of the oily dipentylaminopropionic acid ester which is saponified with lN aqueous sodium hydroxide solution to give a yield of 56% of theory of * Trade Mark 1~ .
hr 3l~3 ~6 the desired acid, m.p. 47 - 49C.
~.
diphosphonic acid.
S In a manner analogous to that described in Reference Example 1, from 3-~-methyl-N-nonylaminopropionic acid there is obtained the corresponding diphosphonate in a yield of 10% of theory, m.p. 159C. with sintering, 178 - 184 C., Mrel = 0-22-l'he ~tarting material is obtained as follows:
Nonylamine i9 reacted~with benzaldehyde to give the oily Schiff base in a yield of 9~% of theory. Hydrogenation with palladium-charcoal catalyst gives l~-benzyl-N-nonyl-amine as an oil in a yield of 94% of theory. From this, with formaldehyde and formic acid, there is-obtained the oily N-benzyl-N-methyl-N-nonylamine in a yield of 98~ of theory. Hydrogenolytic splitting off of the benzyl radical with palladium-charcoal catalyst gives a quantitative yield of the secondary amine in the form of an oil which is reacted with methyl acrylate and saponified in the manner described in Example 1. The yield of the oily ester is 81% of theory and that of the pasty acid is 95O/o of theory.
Exam~le 3.(Reference) 2S 3-~N-Cyclohexyl-N-methylamino~ hydroxy~ropane~
di hos honic acid.
15 g. 3-N-Cyclohexyl-N-methylaminopropionic acid ~ 1 73~
. ., "~prepared from N-cycloh~yl-N-methylamine (commercially - . . available) and methyl acrylate in toluene, yield oE
e~ter 76% o~ theo~y, m.p. 131 - 134C., yield of acid 92% of theory, m.p. 101 - 105C,) are heated to 80C.
with 13.3 g. phosphorous acid. The melt i5 mixed with - 14.1 ml. phosphorus trichloride and kept at the same - temperature for 16 hours. 240 ml. water are then added thereto and the reaction mixture i~ stirred for 1 day at 100C. It is then filtered, the filtrate i~ concen-trated in a vacuum and the oil obtained is poured into 1 litre of acetone, c~ystallisation thereby commencing.
~he crystals are dissolved in water and puriied by ion exchanger chromatography in the manner described in Example 1~ Yield 4.5 g. ~16~90~o of theory) as mono-lS hydrate, m.p. 142C. with sintering, 182 C. (decomp.), Mrel Example 4. (Reference) 1 g. 3-N-Cyclohexylaminopropane-l-hydroxy-l,l-diphosphonic acid is suspended in 30 ml. methylene chloride, 2.5 ml. of a concentrated aqueous solution of sodium hydroxide are added thereto and, with cooling, mixed with 1 g. tetrabutylammonium hydrogen suLphate and 0.3 ml. dimethyl sulphate. The reaction mixture is then vigorously stirred for several hours at ambient temperature. After working up in the usual manner, the identicity of the product obtained with that prepared according to Example 3 is demonstrated by mass spectro- ;
F
.
~: ;. . .
673~
., .
scopy ater siLylation.
The diphosphonic acid used as starting material i9 obtained a~ ~ollows: Cyclohexylamine is reacted with acrylic acid in pyridine to give a yleld of 7~/0 - 5 of theory of 3~N-cyclohexylaminopropionic acid, m.p.
170 - 171C~ The reaction with phosphorou~ acid and phosphorus trichloride gives a yield of 31% of theory of the diphosphonic acid, m.p. 164C. (decomp.l.
Ex~ple ~. (Reference) 10 3-(N Cvc~ohexylmethvl-N-methYlamino)-propane-l-hydroXV- ;`
l,l-diphos~honic acid., 3 ~N-Cyclohexylmethyl-N-methylamino)-propionic acid (prepared ~rom N-benzyl-N-methylamine by hydrogen-ation with platinum catalyst, yield 70% of theory, b.p.
60C./16 mm.Hg reaction with methyl acrylate in toluene, yield 37% of theory o~ methyl 3-(N-cyclohexyl-methyl-~-methylamino)-propionate, saponification with lN aqueous sodium hydroxide solution to give the acid in a yield of 63% o~ theory, m.p. 98 - 102C,) is reacted analogously to Example 3 with phosphorous acid/
phosphorus trichloride to give the diphosphonic acid in a yield of 34% of theory, m.p. 180 - 194C. (decomp.), ~réi ~ 0.31.
~.
di~ ~ acid.
In a manner analogous to that descxibed in i739 Example 3, ~rom 3~N-nonyl-N-propylaminopropionic acid there is obtained the correi~po~ding diphosphonic acid in a yield of 50% of theory, m.p. 100 -- 105C., ~ M 1 = o.23.
- The starting material is obtained ais follows:
2 mole nonylamine are reacted with 1 mole propionyl - chloride to give a quantitative yield o~ the acid amide whlch is reduced with lithium aluminium hydride tD give the secondary amine in a yield of 71% of theory, b.p.
113 - 117C./16 n~.Hg. l mole N-Ilonyl-N-propylamine i9 reacted with 3 mole methyl acrylate in toluene to give an oil in a yield of 81% of theory whIch i9 saponified with lN aqueous sodium hydroxide solution - to give the desired acid in a yield of 14% of theory, m.p. 45 - 47C.
.(Reference) 500 mg. of the diphosphonic acid prepared accord-ing to Example 1 are suspended in 5 ml. water, dissolved with 2.68 ml. 1~ aqueous sodium hydroxide solution, concentrated somewhat and brought to crystallisation by pouxing into aretone. There are thus obtained 440 mg. (78% of theory) of the disodium salt of 1-hydroxy-3-(N,N-dipentylamino)-propane~ diphoisphonic acid in the form of the monohydrate. The meltiny point is above 300C.
Exam~ eference) ~ '~
di~hos~honic acid.
~ .
~L2~ 3~
2 mole nonylamine are reacted with 1 mole valeroyl chloride in diethyl ether, the su3pension is filtered ~ff with suction, the filtrate is evapoxated and N-nonyl-valeric acid amide is thus obtained quantitatively, m.p.
29 - 31C. Reductlon with 1.65 mole lithium aluminium hydride in diethyl ether gives a colourle~s oil in a yield of 78% of theory, b.p. 142 ~ 1~6 Co/16 mm.Hg.
The addition of this N-nonyl-N-pentylamine to methyl acrylate (oil, yield 96% of theory) an~ subsequent ~aponification with lN aqueous sodium hydroxide solution gives a yield of 6~% o~ theory of pasty 3-(N-nonyl-~-pentylamino)-propionic acid ~hich is reacted analogously to Example 3 to give the diphosphonic acid, yield 87%
of theory; m.p. 168 - 17~ C., Mrel = 0.14.
Example 9.
; In a manner analogous to that described in Example 2, there are prepared:
yield m.p.
A. In ~ products:
20 N-benzylidenepentylamine 94% oil N-benzyl-N-pentylamine 74% paste N-benzyl-N-methyl-N-pentylamine 95% oil ~-methyl-N-pentylamine 49% oil methyl 3-(N-methyl-N-pentylamino)- 93% oil propionate 3-(N-methyl-N-pentylaminO)-propionic 34% deliquescent acid crystals ~L;2~'Fi'7~9 ~ yield mO p .
l-hydroxy-3-(N-methyl N-pentylamino)- Mrel 84 C.
propan~-l,l-diphosphonic acid 0 44 decomp.
S B. I termediate products:
N-benzylideneisobutylamine 96% oil N-benzyl-N-isobutylamine 71% oil ~-benzyl-N-isobutyl-N-methylamine 93% oil N-isobutyl-N-methylamine 96% oil 10 methyl 3-(N-isobutyl~N-methylamino)- 9~/ oil propionate 3-(N-isobutyl-N-methylamino)- S7% oil propionic ~cid End product:
1-hydroxy-3-lN-isobutyl-N-methylamino)- Mrel 140C
propane-l,l-diphosphonic acld decomp.
yield C. Intermediate products(Reference):
N-benzylidenehexadecylamine 85% oil 20 N-benzyl-N-hexadecylamine 76% wax N-benzyl-N-hexadecyl-N-methylamine 93% oil N-hexadecyl-N-methylamine 98% wax methyl 3-(N-hexadecyl-N-methylamino)- 100% wax propionate 3-(N-hexadecyl-N-methylamino)- 37% 58-60C.
propionic acid End ~roduct:
3-(N-hexadecyl-N-methylamino)-propane- Mrel 198-254C.
l-hydroxy-l,l-diphosphonic acid o,l decomp.
72%
~2~3~
The oily intermediate products are further reacted without distillation~ The purification of the end products is carried out by ion ~xchange chromatography.
Ex ~ . (Reference) 3_N/N ~ propane-l-hydroxy~ diphosphonic acid.
In a manner analogous to that de~cribed in Reference Example 3, from 3-N,N-dinonylaminopropionic acid there i9 obtained the corresponding diphosphonic acid as the hemihydrate in a yield of 49% of theorY; m.p. 83C.
sintsrs, 161 - 171C,,melts with gas evolution, ~rel =
0.16.
The reaction sequence for the preparation of the starting material is analogous to that described in Example 6:
pelargonic acid N-nonylamide, yield 100% o~ theory, m.p, 52 - 55C.
N,N-dinonylamide, yield 79% of theory, m.p. 37 - 39C.
methyl 3-N,N-dinonylamihopropionate, yield 71% of theory, oil 3~N,~-dinonylaminopropionic acid, yield 180/o of theory, deliquescent crystals.
Example 11~ (Reference) l-Hydroxy-3=(N-meth~l-N-propylamino)-propane-l~l-di hos honic acid _~-: In a manner analogous to that described inReference Example 3, from 3-(~-methyl-N-propylamino)-propionic F
~2~7~9 acid there i~ obtained the corresponding diphosphonic acid in a yield of 35% of theory in the form of the 3es~uihydrate, m.p. 108C. (decomp,) Mrel = 0.4.
The starting material is obtained as follows:
N-methyl-N-propylamine (J.A.C.S., 79, 4720/1957) is reacted, analogously to Example 1, with methyl acrylate and the ester obtained in a yield of 840/o of theory is, without distillation, saponified with lN a~ueous sodium hydroxide solution. The oily acid is thus obtained in a yield of 92% of theory and is used without further purification.
.(Reference) l-Hydrox~-4-(N,N-di-3-methylbut~lamino)-butane-1,1-di~hosphonic acid.
4 g. 4-~mino-1-hydroxybutane-1,1-diphosphonic acid are dissolved in 64 ml. lN aqueous sodium hydroxide solution, mixed with 3.8 ml. isovaleraldehyde and, after the addition of 2.5 g. of 10% palladium-charcoal, hydrogenated at a pres9ure of 5 bar. The course of the reaction is monitored electrophoretically until the starting material has disappeared. ~he reaction mixture is filtered, acidified with Ambe~Lite*R 120 (H+ form~
and evaporated until crystallisation commences, 1.3 g.
of crystals thus being obtained in a yield of 20% of ; 25 theory, m.p. 225 - 227C. (decomp.), Mrel = 0.39.
l-Hydroxy-4-(N-3-methylbutylamino)-butane-1,1-diphosphonic acid remaining in the mother liquor, which * Trade mark 73~
i~ formed a~ an intenmediate, can be u~ed again ~or the reductive alkylation.
~. .
3-(N-Benzyl-N-methylamino)-propane-l-hydroxy-~
S . ' Analogously to Example 3, from 3-~-benzyl-N-methylaminopropionic acid there is obtained the de~ired diphosphonic acid as monohydrate in a yield o~ 360/o of theory, decomposition point 117C. Mrel - 0.37.
~rhe s~arting material i9 ob~ained as follows:
N-~enzyl-N-methylamine is reactecl with methyl acrylate analogously to Example 1 and the ester obtained in a yield of 76% of theory i9, without distillation, sapon-ified with lN aqueous sodium hydroxide solution~ The oily acid i9 thus obtained in a yield of 67% o~ theory and is used without further purification.
~; Exam~le 14. ~Reference) 3-(N Dod~ -N meth~ no)-~ropane-l-hydro~y-~l-diphosphonic acid.
Analogously to Example 3, from 3-N-dodecyl-N-methylaminopropionic acid there is obtained the desired compound in a yield of 28% of theory decomposition point 200 - 216C. Mrel = 0.1.
The starting material is obtained as follows:.
The oily Schiff base obtained from dodecylamine and benzaldehyde (yield 81% of theory) is hydrogenated with palladium catalyst to give the oily ~-benzyl compound ... ~i ~
~2~S73~
in a yield of 74% of theory~ The reductive alkylation with formalin-formic acid gives the tertiary amine, which is also oily, in a yield of 82% of theory. ~he catalytic removal of the benzyl radical by hydrogenolysi~
is quantitative. The oily secondary amine is reacted directly with methyl acrylate to give a pa~ty product in a yield of 50% of theory which is saponified without purification. The desired acid i~ obtained as a viscous mas~ in a yield of 39% of theory and i~ used directly.
" 10' ~
3-(N ~ ropYla ~ r ~ =
diphosphonic acid.
Analogously to Example 3, from 3-(N-benzyL-N-propylamino)-propionic acid there is obtained the desired compound in a yield of 35% of theory, m~p~
~ 112 - 115C. (decomp.), Mrel - 0.33.
- The starting material is obtained as follows:
The oily Schiff base from propylamine and benzaldehyde (yield 86% of theory) iS hydrogenated in the presence o palladium catalyst and gives N-benzyl-~-propylamine in a yield of 81% of theory. The oily secondary amine is now reacted with methyl acrylate to give the oily ester in a yield of 69% of theory from which, by alkaline saponification, there is obtained the acid, which is also an oil, in a ~ield of 88% of theory.
Exam~_e 15 A. (Reference) In a manner analogous to that described in ~L2~$7~9 Example 14, from isopropylamine there is obtained 3-(N-isopropyl-N-methylamino)-propionic acid in a yield o~
76% of theory (m.p, 56 - 59C.) and from this there is obtained l-hydroxy-3-~-isopropyl-N-methylamino)-propane-l,l-diphosphonic acid in a yield of 64% of theory m.p. 215 - 219C. (decomp.); Mrel = 0.41.
Example 16.
In a manner analogous to that de~crihed in Example 2, there are prepared:
10 A, Intermediate products:
, yield m.p.
N-benzylldenel~opropylamine 81% oil N-benzylisopropylarnine 83% oiL
N-benzyl-N-isopropyl-N-methylamine98% oil 15 N-i~opropyl-N-methylamine 100% oil m~thyl 3-(N-isopropyl-N-methyl- 51% oil amino)-propionate 3-(N-isopropyl-N-methylamino)- 76% 56 59C
propionic acid 20 End product (Reference):
l-hydroxy-3-(N-isopropyl-N-methyl- 64% 215-219C
amino)-propane-1,1-diphosphonic acid rel = 0.41 ~ ' .
25 N-benzylidene-2-butyla~ine 89% oil ~ N-benzyl-2-butylamine 92% oil - N-benzyl-N-2-butyl-N-methylamine 85% oil N-2 butyl-N-methylamine, HCl 98% 40-46C.
methyl 3-(~-2-butyl-N-methylamino)-88% oil propionate - 2~ -yield m.p.
3-t~-2-butyl-N-methylamino)- 95% oil propionic acid End product ( Ref erence):
3-(N-2-butyl-N-methylamino)-propane- 39% 95-lOS C.
l-hydroxy-l,l-diphosphonic acid Ç. Inter~9¦~5~_L~y~
methyl 3-N-butylaminopropionate, 75% oil b.p. 95-100 C./20 mm.Hg methyl 3-(N-butyl-N-methylamino)- oil pro~ionate 3-(N-butyl-N-methylamino)-propionic 78% oil acid (yield re~erred to first intermediate product) End ~roduct (Reference):
3-(N-butyl-N-meth~lamino)-propane- 65% 116-121C.
l-hydroxy-l,l-diphosphonic acid Mrel D. Intermediate_product:
4-(N-methyl-~-nonylamino)-butyric acid 47% oil End product (ReEerence):
l-hydroxy-4-(N-methyl-N-nonylamino)- O
butane-l,l-diphosphonic acid 11% 300 C.
disodium salt dihydrate 25 Mrel = 0.25 E. Intermediate ~roducts:
3-N-undecylaminopropionic acid 62% 76-~0C.
; 3-N~methyl-N-undecylaminopropionic acid 59% wax End product (Reference):
30 1-hydroxy-3-N-methyl-N-undecylamino)- 238C
propane-l,l-diphosphonic acid 23%
dipotassium salt dihydrate foamlng ~73~
-o2,~~
The oily intermediate products are further reacted directly without distillation. I~e structure i~ verified spectroscopically. The end products are purified by ion exchanger chromatography~
The Patent Specifications referred to herein are more fully identified as follows:
1. DE 1,813,659 Inventors : Francis, Marion David, Cincinnati, Ohio, U.S.A.
10 Assignee : The Procter and Gamble Co.
U.S.A.
Application Date: : July 3, l9fi9.
Published : December 10, 1986.
Canadian Counterpart : No. 946,290.
2. BE 896,391 Assignee : Instituto Gentili S.P.A., Pisa, Italy.
Application Date : April 14, 1983.
U.S. Counterpart : No. 4,621,077 20 3. DE 2,534,391 Inventors : Blum, Helmut et al.
Assignee : Henkel and Cie GmbH, Dusseldorf West Germany Application Date : August 1, 1975.
Laid Open : February 17, 1977.
U.S. Counterpart : No~ 4,054,598 '.
~6~739 EP 96,931 Inventors : Benedict, James John et al.
Assignee : Mallinckrodt Inc., St. Louis, U.S.A.
Application Date : June 7, 1983~
Laid Open : December 28, 1983.
.~
and evaporated until crystallisation commences, 1.3 g.
of crystals thus being obtained in a yield of 20% of ; 25 theory, m.p. 225 - 227C. (decomp.), Mrel = 0.39.
l-Hydroxy-4-(N-3-methylbutylamino)-butane-1,1-diphosphonic acid remaining in the mother liquor, which * Trade mark 73~
i~ formed a~ an intenmediate, can be u~ed again ~or the reductive alkylation.
~. .
3-(N-Benzyl-N-methylamino)-propane-l-hydroxy-~
S . ' Analogously to Example 3, from 3-~-benzyl-N-methylaminopropionic acid there is obtained the de~ired diphosphonic acid as monohydrate in a yield o~ 360/o of theory, decomposition point 117C. Mrel - 0.37.
~rhe s~arting material i9 ob~ained as follows:
N-~enzyl-N-methylamine is reactecl with methyl acrylate analogously to Example 1 and the ester obtained in a yield of 76% of theory i9, without distillation, sapon-ified with lN aqueous sodium hydroxide solution~ The oily acid i9 thus obtained in a yield of 67% o~ theory and is used without further purification.
~; Exam~le 14. ~Reference) 3-(N Dod~ -N meth~ no)-~ropane-l-hydro~y-~l-diphosphonic acid.
Analogously to Example 3, from 3-N-dodecyl-N-methylaminopropionic acid there is obtained the desired compound in a yield of 28% of theory decomposition point 200 - 216C. Mrel = 0.1.
The starting material is obtained as follows:.
The oily Schiff base obtained from dodecylamine and benzaldehyde (yield 81% of theory) is hydrogenated with palladium catalyst to give the oily ~-benzyl compound ... ~i ~
~2~S73~
in a yield of 74% of theory~ The reductive alkylation with formalin-formic acid gives the tertiary amine, which is also oily, in a yield of 82% of theory. ~he catalytic removal of the benzyl radical by hydrogenolysi~
is quantitative. The oily secondary amine is reacted directly with methyl acrylate to give a pa~ty product in a yield of 50% of theory which is saponified without purification. The desired acid i~ obtained as a viscous mas~ in a yield of 39% of theory and i~ used directly.
" 10' ~
3-(N ~ ropYla ~ r ~ =
diphosphonic acid.
Analogously to Example 3, from 3-(N-benzyL-N-propylamino)-propionic acid there is obtained the desired compound in a yield of 35% of theory, m~p~
~ 112 - 115C. (decomp.), Mrel - 0.33.
- The starting material is obtained as follows:
The oily Schiff base from propylamine and benzaldehyde (yield 86% of theory) iS hydrogenated in the presence o palladium catalyst and gives N-benzyl-~-propylamine in a yield of 81% of theory. The oily secondary amine is now reacted with methyl acrylate to give the oily ester in a yield of 69% of theory from which, by alkaline saponification, there is obtained the acid, which is also an oil, in a ~ield of 88% of theory.
Exam~_e 15 A. (Reference) In a manner analogous to that described in ~L2~$7~9 Example 14, from isopropylamine there is obtained 3-(N-isopropyl-N-methylamino)-propionic acid in a yield o~
76% of theory (m.p, 56 - 59C.) and from this there is obtained l-hydroxy-3-~-isopropyl-N-methylamino)-propane-l,l-diphosphonic acid in a yield of 64% of theory m.p. 215 - 219C. (decomp.); Mrel = 0.41.
Example 16.
In a manner analogous to that de~crihed in Example 2, there are prepared:
10 A, Intermediate products:
, yield m.p.
N-benzylldenel~opropylamine 81% oil N-benzylisopropylarnine 83% oiL
N-benzyl-N-isopropyl-N-methylamine98% oil 15 N-i~opropyl-N-methylamine 100% oil m~thyl 3-(N-isopropyl-N-methyl- 51% oil amino)-propionate 3-(N-isopropyl-N-methylamino)- 76% 56 59C
propionic acid 20 End product (Reference):
l-hydroxy-3-(N-isopropyl-N-methyl- 64% 215-219C
amino)-propane-1,1-diphosphonic acid rel = 0.41 ~ ' .
25 N-benzylidene-2-butyla~ine 89% oil ~ N-benzyl-2-butylamine 92% oil - N-benzyl-N-2-butyl-N-methylamine 85% oil N-2 butyl-N-methylamine, HCl 98% 40-46C.
methyl 3-(~-2-butyl-N-methylamino)-88% oil propionate - 2~ -yield m.p.
3-t~-2-butyl-N-methylamino)- 95% oil propionic acid End product ( Ref erence):
3-(N-2-butyl-N-methylamino)-propane- 39% 95-lOS C.
l-hydroxy-l,l-diphosphonic acid Ç. Inter~9¦~5~_L~y~
methyl 3-N-butylaminopropionate, 75% oil b.p. 95-100 C./20 mm.Hg methyl 3-(N-butyl-N-methylamino)- oil pro~ionate 3-(N-butyl-N-methylamino)-propionic 78% oil acid (yield re~erred to first intermediate product) End ~roduct (Reference):
3-(N-butyl-N-meth~lamino)-propane- 65% 116-121C.
l-hydroxy-l,l-diphosphonic acid Mrel D. Intermediate_product:
4-(N-methyl-~-nonylamino)-butyric acid 47% oil End product (ReEerence):
l-hydroxy-4-(N-methyl-N-nonylamino)- O
butane-l,l-diphosphonic acid 11% 300 C.
disodium salt dihydrate 25 Mrel = 0.25 E. Intermediate ~roducts:
3-N-undecylaminopropionic acid 62% 76-~0C.
; 3-N~methyl-N-undecylaminopropionic acid 59% wax End product (Reference):
30 1-hydroxy-3-N-methyl-N-undecylamino)- 238C
propane-l,l-diphosphonic acid 23%
dipotassium salt dihydrate foamlng ~73~
-o2,~~
The oily intermediate products are further reacted directly without distillation. I~e structure i~ verified spectroscopically. The end products are purified by ion exchanger chromatography~
The Patent Specifications referred to herein are more fully identified as follows:
1. DE 1,813,659 Inventors : Francis, Marion David, Cincinnati, Ohio, U.S.A.
10 Assignee : The Procter and Gamble Co.
U.S.A.
Application Date: : July 3, l9fi9.
Published : December 10, 1986.
Canadian Counterpart : No. 946,290.
2. BE 896,391 Assignee : Instituto Gentili S.P.A., Pisa, Italy.
Application Date : April 14, 1983.
U.S. Counterpart : No. 4,621,077 20 3. DE 2,534,391 Inventors : Blum, Helmut et al.
Assignee : Henkel and Cie GmbH, Dusseldorf West Germany Application Date : August 1, 1975.
Laid Open : February 17, 1977.
U.S. Counterpart : No~ 4,054,598 '.
~6~739 EP 96,931 Inventors : Benedict, James John et al.
Assignee : Mallinckrodt Inc., St. Louis, U.S.A.
Application Date : June 7, 1983~
Laid Open : December 28, 1983.
.~
Claims (37)
1. A diphosphonate of the general formula:
(I) wherein:
R1 is methyl or n-propyl; and R2 is isobutyl, pentyl, nonyl or benzyl;
or a pharmaceutically acceptable, pharmacologically compatible salt thereof.
(I) wherein:
R1 is methyl or n-propyl; and R2 is isobutyl, pentyl, nonyl or benzyl;
or a pharmaceutically acceptable, pharmacologically compatible salt thereof.
2. A diphosphonate according to claim 1, wherein R1 is a methyl or a pharmaceutically accept-able, pharmacologically compatible salt thereof.
3. 1-Hydroxy-3-(N-methyl-N-nonylamino)-propane-1,1-diphosphonic acid and pharmaceutically accept-able, pharmacologically compatible salts thereof.
4. 1-Hydroxy-3-(N-methyl-N-pentylamino)-propane 1,1-diphosphonic acid and pharmaceutically accept-able, pharmacologically compatible salts thereof.
5. 1-Hydroxy-3-(N-isobutyl-N-methylamino)-pro-pane-1,1-diphosphonic acid and pharmaceutically acceptable, pharmacologically compatible salts thereof.
6. 3-(N-Benzyl-N-methylamino)-propane-l-hydroxy 1,1-diphosphonic acid and pharmaceutically accept-able, pharmacologically compatible salts thereof.
7. A pharmaceutical composition containing at least one disphosphonate of formula (I), as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable, pharmacologically compatible salt there-of, in a pharmacologicall.y effective and acceptable amount, in association wih a pharmaceutically and pharmacologically acceptable carrier therefor.
8. A pharmaceutical composition for the treatment or prophylaxis of calcium metabolism disturbance or disease comprising an effective and acceptable amount of a compound or salt of claim 3, 4, 5 or 6, in association with a pharmaceutically acceptable carrier.
9. The use of a disphosphorlate of formula (I), as defined in claim 1, 2, 3, 4, 5 or 6, or a pharma-ceutically acceptable, pharmacologically compatible salt thereof, for the preparation of a pharmaceutical composition.
10. The use of a diphosphonate of formula (I), as defined in claim 1, 2, 3, 4, 5 or 6, or a pharma-ceutically acceptable, pharmacologically compatible salt thereof, for the treatment or prophylaxis of disturbance or disease of the calcium metabolism.
11. Use of a compound or salt as defined in claim 3, 4, 5 or 6, for the treatment or prophylaxis of disturbance or disease of the calcium metabolism.
12. A process for the preparation of a disphos-phonate of formula (I):
(I) in which R1 is methyl or n-propyl; and R2 is iso-butyl, pentyl, nonyl or benzyl;
and the pharmaceutically acceptable, pharmacologically compatible salts thereof, comprising:
a) reacting a carboxylic acid of the formula (VIII):
(VIII) in which R1 and R2 are as defined above, with a mixture of phosphorous acid or phosphoric acid and a phosphorus halide and subsequently saponifying or hydrolyzing to give a free diphosphonic acid of formula (I); or b) reacting a carboxylic acid chloride of formula (IX):
(IX) in which R1 and R2 are as defined above, with a trialkyl phosphite of the formula (X);
P(OR')3 (X) in which R' is an alkyl radical of 1 to 4 carbon atoms to give an acyl phosphonate of the formula (XI):
(XI) in which R1, R2 and R' are as defined above, and subsequently reacting said acid phosphonate (XI) with a dialkyl phosphite of the formula (XII) (XII) in which R' is as defined above, to give a diphos-phonate of the formula (XIII):
(XIII) in which R1, R2, X and R' are as defined above, and saponifying or hydrolysing the tetraester obtained to give a corresponding acid of formula (I); or c) mono- or dialkylating a compound of the formula (XIV):
(XIV) in which R' is as defined above and R4 is a hydrogen atom or has the same meaning as R2, and saponifying or hydrolysing the tetraester obtained to give a corresponding acid of formula (I);
and, when desired, converting a compound (I) thus obtained into a corresponding pharmacueti-cally acceptable, pharmacologically compatible salt thereof.
(I) in which R1 is methyl or n-propyl; and R2 is iso-butyl, pentyl, nonyl or benzyl;
and the pharmaceutically acceptable, pharmacologically compatible salts thereof, comprising:
a) reacting a carboxylic acid of the formula (VIII):
(VIII) in which R1 and R2 are as defined above, with a mixture of phosphorous acid or phosphoric acid and a phosphorus halide and subsequently saponifying or hydrolyzing to give a free diphosphonic acid of formula (I); or b) reacting a carboxylic acid chloride of formula (IX):
(IX) in which R1 and R2 are as defined above, with a trialkyl phosphite of the formula (X);
P(OR')3 (X) in which R' is an alkyl radical of 1 to 4 carbon atoms to give an acyl phosphonate of the formula (XI):
(XI) in which R1, R2 and R' are as defined above, and subsequently reacting said acid phosphonate (XI) with a dialkyl phosphite of the formula (XII) (XII) in which R' is as defined above, to give a diphos-phonate of the formula (XIII):
(XIII) in which R1, R2, X and R' are as defined above, and saponifying or hydrolysing the tetraester obtained to give a corresponding acid of formula (I); or c) mono- or dialkylating a compound of the formula (XIV):
(XIV) in which R' is as defined above and R4 is a hydrogen atom or has the same meaning as R2, and saponifying or hydrolysing the tetraester obtained to give a corresponding acid of formula (I);
and, when desired, converting a compound (I) thus obtained into a corresponding pharmacueti-cally acceptable, pharmacologically compatible salt thereof.
13. A diphosphonate of formula (I), as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable, pharmacologically compatible salt there-of for use in the treatment or prophylaxis of dis-turbance or disease of the calcium metabolism.
14. A diphosphonic acid of claim 3, 4, 5 or 6, or a pharmaceutically acceptable, pharmacologically compatible salt thereof for use in the treatment or prophylaxis of disturbance or disease of the calcium metabolism.
15. 1-Hydroxy-3-(N-methyl-N-pentylamino)-propane 1,1-diphosphonic acid.
16. A pharmaceutically acceptable, pharmacologically compatible salt of the diphosphonic acid of claim 15.
17. A pharmaceutical composition for the treatment or prophylaxis of calcium metabolism disturbance or disease comprising an effective and acceptable amount of the acid of claim 15, in association with a pharma-ceutically acceptable carrier.
18. A pharmaceutical composition for the treatment or prophylaxis of calcium metabolism disturbance or disease comprising an effective and acceptable amount of the salt of claim 16, in association with a pharmaceutically acceptable carrier.
19. Use of the acid of claim 15, for the treatment or prophylaxis of disturbance or disease of the calcium metabolism.
20. Use of the salt of claim 16, for the treatment or prophylaxis of disturbance or disease of the calcium metabolism.
21. Use of the acid of claim 15, for the manufacture of a medicament for the treatment or prophylaxis of disturbance ox disease of the calcium metabolism.
22. Use of the salt of claim 16, for the manufacture of a medicament for the treatment or prophylaxis of disturbance or disease of the calcium metabolism.
23. 1-Hydroxy-3-(N-methyl-N-pentylamino)-propane 1,1-diphosphonic acid for use in the treatment or prophy-laxis of disturbance or disease of the calcium metabolism.
24. A pharmaceutically acceptable, pharmacologically compatible salt of 1-hydroxy-3-(N-methyl-N-pentylamino)-propane 1,1-diphosphonic acid for use in the treatment or prophylaxis of disturbance or disease of the calcium metabolism.
25. A pharmaceutical composition for the treatment or prophylaxis of osteoporosis comprising an effective and acceptable amount of a compound or salt of claim 3, 4, 5 or 6, in association with a pharmaceutally acceptable carrier.
26. The use of a diphosphonate of formula (I), as defined in claim 1, 2, 3, 4, 5 or 6, or a pharma-ceutically acceptable, pharmacologically compatible salt thereof, for the treatment or prophylaxis of osteoporosis.
27. Use of a compound or salt as defined in claim 3, 4, 5 or 6, for the treatment or prophylaxis of osteoporosis.
28. A diphosphonate of formula (I), as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable, pharmacologically compatible salt thereof for use in the treatment or prophylaxis of osteoporosis.
29. A diphosphonic acid of claim 3, 4, 5 or 6, or a pharmaceutically acceptable, pharmacologically compatible salt thereof for use in the treatment or prophylaxis of osteoporosis.
30. A pharmaceutical composition for the treatment or prophylaxis of osteoporosis comprising an effective and acceptable amount of the acid of claim 15, in association with a pharmaceutically acceptable carrier.
31. A pharmaceutical composition for the treatment or prophylaxis of osteoporosis comprising an effective and acceptable amount of the salt of claim 16, in association with a pharmaceutically acceptable carrier.
32. Use of the acid of claim 15, for the treatment or prophylaxis of osteoporosis.
33. Use of the salt of claim 16, for the treatment or prophylaxis of osteoporosis.
34. Use of the acid of claim 15, for the manufacture of a medicament for the treatment or prophylaxis of osteoporosis.
35. Use of the salt of claim 16, for the manufacture of a medicament for the treatment or prophylaxis of osteoporosis.
36. 1-Hydroxy-3-(N-methyl-N-pentylamino)-propane 1,1-diphosphonic acid for use in the treatment or prophylaxis of osteoporosis.
37. A pharmaceutically acceptable, pharmaco-logically compatible salt of 1-hydroxy-3-(N-methyl-N-pentylamino)-propane 1,1-diphosphonic acid for use in the treatment or prophylaxis of osteoporosis.
#47-09/09/1991
#47-09/09/1991
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863623397 DE3623397A1 (en) | 1986-07-11 | 1986-07-11 | NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DEP3623397.8 | 1986-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1296739C true CA1296739C (en) | 1992-03-03 |
Family
ID=6304949
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000541755A Expired - Lifetime CA1296739C (en) | 1986-07-11 | 1987-07-10 | Diphosphonic acid derivatives, processes for the preparation thereofand pharmaceutical compositions containing them |
| CA000541756A Expired - Lifetime CA1305166C (en) | 1986-07-11 | 1987-07-10 | 1-hydroxy-3-(n-methyl-n-proplylamino)propane-1,1- diphosphonic acid, pharmaceutical compositions and methods of use |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000541756A Expired - Lifetime CA1305166C (en) | 1986-07-11 | 1987-07-10 | 1-hydroxy-3-(n-methyl-n-proplylamino)propane-1,1- diphosphonic acid, pharmaceutical compositions and methods of use |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US4927814A (en) |
| EP (2) | EP0252505B1 (en) |
| JP (2) | JP2563954B2 (en) |
| KR (2) | KR950008997B1 (en) |
| AT (2) | ATE80633T1 (en) |
| AU (2) | AU598279B2 (en) |
| BG (1) | BG60839B2 (en) |
| CA (2) | CA1296739C (en) |
| CS (1) | CS265242B2 (en) |
| DD (1) | DD263992A5 (en) |
| DE (4) | DE3623397A1 (en) |
| DK (2) | DK168629B1 (en) |
| ES (2) | ES2036190T3 (en) |
| FI (2) | FI87221C (en) |
| GE (1) | GEP20084347B (en) |
| GR (2) | GR3000616T3 (en) |
| HK (1) | HK87093A (en) |
| HU (2) | HU201950B (en) |
| IE (2) | IE60345B1 (en) |
| IL (2) | IL83149A (en) |
| LU (1) | LU88844I2 (en) |
| MX (1) | MX9203375A (en) |
| NL (1) | NL960032I2 (en) |
| NZ (2) | NZ221027A (en) |
| PT (1) | PT85301B (en) |
| WO (1) | WO1988000590A1 (en) |
| ZA (1) | ZA874877B (en) |
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